Abnormal accumulation of misfolded Tau protein is tightly linked pathogenically to a group of brain degenerative disorders including Alzheimer's disease (AD) that are collectively called Tauopathies. Currently there is no effective prevention or treatment avenue against these debilitating diseases. Targeted clearance of misfolded, pathogenic Tau species thus represents one potentially vital therapeutic strategy. A flurry of recent studies, corroborating with a long history of clinical observations, have led to the proposal that Huntington's disease (HD), another fatal neurodegenerative disorder caused by an abnormal expansion of a glutamine tract (polyQ) in Huntingtin (HTT) protein, is also a tauopathy disease. Interestingly, while working on the HTT homolog in Drosophila, we found that normal HTT can promote the clearance of certain misfolding-prone Tau species by acting as a scaffold in selective autophagy, a subtype of autophagy-lysosomal pathway that requires cargo receptors such as p62/SQSTM1 to recognize and target specific cytosolic components for lysosomal degradation. Subsequent studies in mammalian cells and in mouse AD models further supported this finding, which, together with the known autophagic phenotypes in HD cells and in mice expressing polyQ-deleted HTT, suggest a scenario that polyQ expansion in HTT disrupts its own activity in promoting selective autophagy and normal Tau turnover, leading to the Tau pathology. Such a hypothesis not only supports the HTT-mediated autophagy pathway as a converging mechanism linking HD and Tauopathy, but also raises the promise of harnessing this conserved innate protective pathway for targeted removal of pathogenic Tau in Tauopathies. In this joint R01 application, we will use our established assays in the complementary Drosophila, cellular, and mouse model systems to rigorously and systematically test this hypothesis at the genetic, biochemical and functional levels. Taking advantage of the conserved HTT and autophagy pathways, as well as the availability of a plethora of Tau models and Tau toxicity assays established in Drosophila, we will use flies as an in vivo tool to evaluate the effect of polyQ lengths on the autophagic function of HTT, and to examine the discrete Tau species to search for the ones that can be degraded by the HTT-mediated selective autophagy and for their common signatures; Using mammalian cell-based assays, we will validate the findings from the flies and also probe the molecular mechanisms underlying the modulatory role of the polyQ stretch on HTT activities. Finally, by manipulating Tau and HTT in the well-characterized mouse HD and AD models, we will directly validate our hypothesis and findings in an in vivo setting that is physiologically closer to humans. Completion of this project will reveal novel mechanistic insight into the crosstalk between Tauopathy and HD, and establish the feasibility of future pharmacological exploitation of the novel selectively autophagy pathway to combat morbidity and mortality arising from Tau-associated AD and other Tauopathies.